Efficacy of Daptomycin versus Vancomycin in an Experimental Model

of Foreign-Body and Systemic Infection Caused by Biofilm Producers

and Methicillin-Resistant Staphylococcus epidermidis
J. Domínguez-Herrera, F. Docobo-Pérez, R. López-Rojas, C. Pichardo, R. Ruiz-Valderas, J. A. Lepe, and J. Pachón
Unit of Infectious Diseases, Microbiology, and Preventive Medicine, and Institute of Biomedicine of Sevilla (IBiS), University Hospital Virgen del Rocío/CSIC/University of
Seville, Seville, Spain

Staphylococcus epidermidis is a frequent cause of device-associated infections. In this study, we compared the efficacy of dapto-
mycin versus vancomycin against biofilm-producing methicillin-resistant S. epidermidis (MRSE) strains in a murine model of
foreign-body and systemic infection. Two bacteremic biofilm-producing MRSE strains were used (SE284 and SE385). The MIC of

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daptomycin was 1 mg/liter for both strains, and the MICs of vancomycin were 4 and 2 mg/liter for SE284 and for SE385, respec-
tively. The in vitro bactericidal activities of daptomycin and vancomycin were evaluated by using time-kill curves. The model of
foreign-body and systemic infection of neutropenic female C57BL/6 mice was used to ascertain in vivo efficacy. Animals were
randomly allocated into three groups (n ⴝ 15): without treatment (controls) or treated with daptomycin at 50 mg/kg/day or van-
comycin at 440 mg/kg/day. In vitro, daptomycin showed concentration-dependent bactericidal activity, while vancomycin pre-
sented time-dependent activity. In the experimental in vivo model, daptomycin and vancomycin decreased liver and catheter
bacterial concentrations (P < 0.05) and increased the survival and the number of sterile blood cultures (P < 0.05) using both
strains. Daptomycin produced a reduction in the bacterial liver concentration higher than 2.5 log10 CFU/g compared to vanco-
mycin using both strains, with this difference being significant (P < 0.05) for infection with SE385. For the catheter bacterial
concentrations, daptomycin reduced the concentration of SE284 3.0 log10 CFU/ml more than did vancomycin (P < 0.05). Dapto-
mycin is more effective than vancomycin for the treatment of experimental foreign-body and systemic infections by biofilm-
producing methicillin-resistant S. epidermidis.

S taphylococcus epidermidis is a common nosocomial and health

care-associated pathogen in several infections, causing impor-
tant morbidity, mortality, and/or health care costs. Thus, it is the
most important cause of infections of orthopedic prostheses, ac-
counting for approximately 40% of all cases, and between 30%
and 50% of catheter-related bacteremias are caused by coagulase-
negative Staphylococcus (CNS) strains (19, 26). Other severe
and/or frequent nosocomial and health care-associated infections
are also caused by CNS, being the etiology in the 22.7% of endo-
carditis infections (9, 13) and in 37 to 78% of cerebrospinal fluid
shunt-associated infections (4, 11).
Moreover, the high frequency of methicillin-resistant S. epider-
midis (MRSE) is an important therapeutic problem. Thus, data
from the National Nosocomial Infections Surveillance System
(NNIS) in the United States from 1992 to 2004 revealed that 89.1%
of the coagulase-negative staphylococci isolated in intensive care
units (ICUs) presented resistance to methicillin (16). Vancomycin is
the recommended treatment for infections caused by MRSE (14), but
the emergence of strains with reduced susceptibility to vancomycin
(1) makes the evaluation of other therapeutic alternatives necessary.
Among them, daptomycin, a cyclic lipopeptide with bactericidal ac-
tivity against Gram-positive bacteria (http://www.accessdata.fda.gov
/drugsatfda_docs/label/2010/021572s022s023s024s027s030s032lbl
.pdf), represents a clinical therapeutic option (14).
On the other hand, the ability of S. epidermidis to produce
biofilms provides significant resistance to antibiotics and impairs
the host innate immune response (23). In these situations, the use
of an antimicrobial able to cross the biofilm enhances the efficacy
of the treatment. In this context, the ability of daptomycin to
penetrate rapidly into the biofilm produced by S. epidermidis is
well known (21), in contrast to the reduced ability of vancomycin
to do so (20). Moreover, the higher level of activity of daptomycin
than that of vancomycin was demonstrated previously with an in
vitro dynamic system using a polyurethane intravascular catheter
as a substrate for biofilm growth (7).
Although the efficacy of daptomycin against MRSE has been
analyzed in several experimental studies, such as a model of
experimental endocarditis in rabbits (8) and a model of tissue
cage infection in guinea pigs (17), the role of daptomycin
against biofilm-producing MRSE in catheter-related infections
remains unknown.
Thus, the aim of the present study was to compare the efficacy
of daptomycin to that of vancomycin in an experimental model of
foreign-body infection in neutropenic mice, causing bacterial sys-
temic infection, by biofilm-producing MRSE strains with reduced
susceptibility to vancomycin.
(This work was presented at the 21st European Congress of
Clinical Microbiology and Infectious Diseases/27th International
Congress of Chemotherapy, Milan, Italy, 7 to 10 May 2011 [5a].)
Received 26 August 2011 Returned for modification 27 September 2011
Accepted 16 November 2011
Published ahead of print 28 November 2011
Address correspondence to J. Domínguez-Herrera, judoher@yahoo.es.
J. Domínguez-Herrera and F. Docobo-Pérez contributed equally to this work.
Copyright © 2012, American Society for Microbiology. All Rights Reserved.
doi:10.1128/AAC.05606-11

0066-4804/12/$12.00 Antimicrobial Agents and Chemotherapy p. 613– 617 aac.asm.org 613

Domínguez-Herrera et al.
MATERIALS AND METHODS
Bacterial strains. Two MRSE strains (SE284 and SE385) were selected
from 20 consecutive bacteremic isolates based on susceptibility to dapto-
mycin and vancomycin and their ability to produce biofilms (3, 2, 6).
Antibiotics. For the in vitro studies, standard laboratory daptomycin
powder was supplied by Novartis Pharma AG (Basel, Switzerland), and
vancomycin was supplied by Sigma-Aldrich (Madrid, Spain). For the in
vivo studies, commercial vials of daptomycin (Novartis Pharma AG, Ba-
sel, Switzerland) and vancomycin (Laboratorios Normon S.A., Tres Can-
tos, Spain) were used.
Animals. Female C57BL/6 mice weighing 18 to 20 g were obtained
from the University of Seville, having a sanitary status of murine pathogen
free. Animals were housed in regulation cages and given access to food and
water ad libitum. Mice were rendered neutropenic by the injection of
cyclophosphamide (Baxter Oncology GmbH, Halle, Germany) intraperi-
toneally (i.p.) 4 days (150 mg/kg of body weight) and 1 day (100 mg/kg)
before the experiments (5) and were housed and manipulated in sterile
conditions. The study was approved by the Ethics and Clinical Research
Committee of the University Hospitals Virgen del Rocío, Seville, Spain.
In vitro studies. (i) Susceptibility testing. The MIC was determined
in duplicate for each bacterial strain using a standard broth microdilution
method according to CLSI reference methods (3). Staphylococcus aureus
ATCC 29213 was used as a control strain.
(ii) Time-kill studies. The bactericidal activities of daptomycin and
vancomycin were evaluated by using concentrations of 1⫻ MIC and the
maximal serum concentration in mice (Cmax). The initial inocula were 106
CFU of each strain/ml. Bacterial growths were quantified at 0, 2, 4, 8, and
24 h after incubation at 37°C by plating 10-fold dilutions onto plates of
Columbia agar with 5% sheep blood. The limit of detection was 10 CFU/
ml, corresponding to 1 log10 CFU/ml. An antimicrobial was considered
bactericidal when a 3-log10 decrease in the CFU/ml was reached compared
with the CFU/ml of the initial inoculum (15). In vitro daptomycin studies
were performed with Mueller-Hinton broth (MHB), cation adjusted to a
final Ca2⫹ concentration of 50 ␮g/ml according to standard methodolo-
gies (3).
(iii) Biofilm characterization. The ability of the MRSE strains to pro-
duce a biofilm in vitro was determined by using phenotypic methods.
Phenotypic characterization was performed by use of tryptic soy agar
plates with sucrose (50 g/liter) and Congo red (0.8 g/liter) (6). Biofilm-
producing strains grew on this medium as black colonies, whereas
biofilm-negative strains grew as red colonies. Also, quantitative biofilm
measurements were performed by a microtiter plate assay, modified from
a method described previously by Christensen et al. (2). Briefly, bacteria
were grown overnight in tryptic soy broth (TSB) and then diluted 1:100 in
TSB with sucrose (50 g/liter), and finally, 96-well culture plates were filled.
After 24 h of incubation at 37°C without shaking, the medium and non-
adhered bacteria were discarded. Plates were then washed three times with
phosphate-buffered saline (PBS), and the remaining bacteria were fixed
by air drying. After staining with a 0.4% solution of crystal violet, the
optical density at 580 nm (OD580) of the adherent biofilm was determined
with a spectrometer plate reader after biofilm solubilization with 95%
ethanol. OD580 values of ⬎0.120 were considered biofilm positive (2). S.
epidermidis ATCC 35983 and S. epidermidis ATCC 35984 were used as
controls for biofilm-positive strains, and S. epidermidis ATCC 27626 was
used as a negative control.
In vivo studies. (i) Pharmacokinetic/pharmacodynamic studies. Serum
antibiotic concentrations in neutropenic noninfected mice were deter-
mined after a single intraperitoneal administration of either 50 mg/kg
daptomycin or 110 mg/kg vancomycin. For groups of three mice for every
time point, blood was extracted from the periorbital plexus in anesthe-
tized mice after 5, 10, 15, 30, 60, 90, 120, 240, 360, 600, 720, 840, 1,080, and
1,440 min. Concentrations of daptomycin were determined by using a
high-performance liquid chromatography (HPLC) method (22). Con-
centrations of vancomycin were determined by using an agar diffusion
bioassay with Bacillus subtilis ATCC 6633 as a control strain (12). The
614 aac.asm.org
Cmax (mg/liter), the area under the concentration-time curve (AUC)
(mg · h/liter), and the terminal half-life (t1/2) (h) were calculated by a
computer-assisted method (PK Functions for Microsoft Excel; J. L. Usan-
sky, A. Desai, and D. Tang-Liu, Department of Pharmacokinetics and
Drug Metabolism, Allergan, Irvine, CA [http://www.boomer.org/pkin
/soft.html]).
A daptomycin dose of 50 mg/kg was chosen to obtain an AUC from 0
to 24 h (AUC0 –24) similar to that in humans after a dose of 6 mg/kg (25).
In the case of vancomycin, a dose of 110 mg/kg was chosen to target an
AUC0 –24 similar to that in humans after doses of 1 g every 12 hours (q12h)
(454 mg · h/liter) (10).
(ii) Animal model. A modified murine model of foreign-body infec-
tion described previously (18) was used to evaluate the efficacies of dap-
tomycin and vancomycin. Briefly, mice were rendered neutropenic, and 1
cm of a sterile polyfluorinated ethylene-propylene catheter was then asep-
tically implanted into the abdominal cavity. Experimental infection was
produced by the intraperitoneal injection of 0.5 ml of a bacterial suspen-
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sion (8.04 ⫾ 0.45 log10 CFU/ml) into the lateral abdominal wall opposite
the operation wound, 15 min after the insertion of the catheter implant.
The treatments started 4 h after the infection. At this time point, the
bacterial burdens were 7.84 ⫾ 0.22 and 8 ⫾ 0.29 log10 CFU/g in liver and
5.01 ⫾ 0.26 and 4.10 ⫾ 0.21 log10 CFU/ml in catheter for SE284 and
SE385, respectively. Also, 100% of blood cultures were positive for both
strains. Animals were randomly included in three different therapeutic
groups of 15 mice each, control (without treatment), daptomycin at 50
mg/kg/day, or vancomycin at 440 mg/kg/day, for both strains. Animals
were treated and monitored during 72 h.
Before the experiment, in order to discard the toxicity of the treat-
ments, two groups of 5 uninfected neutropenic mice received daptomycin
or vancomycin during 72 h.
Immediately after death or sacrifice at the end of the 72-h period,
samples were obtained and processed as follows. Aseptic thoracotomy was
performed, and blood samples were obtained for qualitative blood cul-
tures through cardiac puncture. The peritoneal cavity was aseptically
opened; catheter and liver were then aseptically removed. The catheter
was slowly flushed with 1 ml of sterile saline solution to remove blood and
nonadhered bacteria. Later, the catheter was transferred into 1 ml of ster-
ile saline solution in a tube, which was sonicated for 10 min at 40 to 60 kHz
(Ultrasons 513 water bath sonicator; P-Selecta, Barcelona, Spain). The
liver was homogenized (Stomacher 80; Tekmar Co., Cincinnati, OH) in 2
ml of sterile saline solution. Ten-fold dilutions of homogenized liver and
the resulting catheter-sonicated solution were performed, and the mix-
tures were plated onto Columbia agar with 5% sheep blood for quantita-
tive cultures.
Statistical analysis. Means of bacterial concentrations in liver (log10
CFU/g of tissue) and catheter (log10 CFU/ml) were compared by analysis
of variance (ANOVA) and, when required, by Dunnett and Tukey post hoc
tests. The frequencies of sterile blood cultures and survival were analyzed
by a chi-square test. A P value of ⬍0.05 was considered significant. The
statistical package SPSS, version 15.0, was used (SPSS Inc., Chicago, IL).
RESULTS
In vitro studies. (i) MIC. Both strains were susceptible to dapto-
mycin and vancomycin. The MICs of daptomycin were 1 mg/liter
for both strains, and those of vancomycin were 4 and 2 mg/liter for
SE284 and for SE385, respectively.
(ii) Time-kill studies. The results of the bactericidal assays are
shown in Fig. 1. Daptomycin was bactericidal at Cmax at 4, 8, and
24 h for SE284 and at 8 and 24 h for SE385. Vancomycin was
bactericidal at 24 h for both strains with the two concentrations
used.
(iii) Biofilm characterization. Both strains were biofilm posi-
tive after the Congo red agar plate assay and showed an OD580 of
⬎120 with the crystal violet assay.
Antimicrobial Agents and Chemotherapy
 Daptomycin versus Vancomycin in MRSE Infection Model

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FIG 1 Time-kill curves of daptomycin and vancomycin at 1⫻ MIC and the maximal serum concentration in mice (Cmax). Circles, controls; triangles, 1⫻ MIC;
squares, Cmax.

In vivo studies. (i) Pharmacokinetic/pharmacodynamic respectively. Numbers of both sterile blood cultures and survivors
studies. Pharmacokinetic and pharmacodynamic parameters are were increased in infections with any strain treated with dap-
shown in Table 1. In the case of daptomycin, the dose of 50 mg/kg tomycin or vancomycin compared to those with their control
showed an AUC0 –⬁ of 595.39 mg · h/liter, so a single dose was used groups (P ⬍ 0.05).
to mimic the human dose of 6 mg/kg (AUC0 –⬁ of 598 mg · When the efficacies of both antimicrobials were compared,
h/liter). The vancomycin dose of 110 mg/kg showed an there was a trend toward better results with daptomycin than with
AUC0 –⬁ of 111.36 mg · h/liter; thus four daily doses were used vancomycin in terms of the reduction of the bacterial concentra-
to achieve a similar value of AUC0 –24 h after two doses of 1 g/12 tion in liver or catheter, sterile blood cultures, and survival for
h in humans (454 mg · h/liter). both strains. These differences were significant for the reduction
(ii) Animal model. The efficacies of the different treatments of the bacterial catheter concentration of strain SE284 (P ⬍ 0.05)
are shown in Table 2. For both strains, daptomycin reduced the and for the decrease of the bacterial liver concentration of strain
liver bacterial concentration more than 7 log10 CFU/g and re- SE385 (P ⬍ 0.05).
duced the catheter bacterial concentration approximately 5.5 No mortality was observed for the uninfected neutropenic
log10 CFU/ml with respect to their controls (P ⬍ 0.05). In the case mice included in the toxicity studies receiving daptomycin or van-
of vancomycin, the treatment reduced the liver bacterial concen- comycin during 72 h.
tration approximately 5 log10 CFU/g and reduced the catheter
bacterial concentration 2.87 and 4.78 log10 CFU/ml with respect DISCUSSION
to their control groups (P ⬍ 0.05) for strains SE284 and SE385, The present study evaluates the in vivo therapeutic efficacies of
daptomycin and vancomycin against two biofilm-producing
MRSE strains by using a murine model of foreign-body infection
TABLE 1 Pharmacokinetics and pharmacodynamics of daptomycin and described previously (18). Using this model, both antimicrobials
vancomycin reduced the bacterial concentrations in catheter and liver and in-
No. of Dose Cmax AUC0–⬁ t1/2 AUC0-24/ creased the numbers of sterile blood cultures and survival rates
Antimicrobial xxxd (mg/kg) (mg/liter) (mg · h/liter) (h) MIC ratio with any strain. On the other hand, in the comparison of both
Daptomycin 42 50 162.21 595.39 1.91 595.39a treatments, there was a trend toward better results with daptomy-
Vancomycin 42 110 97.79 111.36 0.57 111.36b cin than with vancomycin for any parameter, which was signifi-
222.72c cant for the bacterial concentrations in the catheter and the liver in
a Parameter calculated for both strains using MICs of daptomycin of 1 mg/liter and a the experiments with strains SE284 and SE385, respectively.
daptomycin dose of 50 mg/kg/day. These in vivo results are in accordance with the early in vitro
b Parameter calculated for strain SE284 using MICs of vancomycin of 4 mg/liter and a
bactericidal activity of daptomycin at Cmax, beginning at 4 and 8 h
vancomycin dose of 440 mg/kg/day.
c Parameter calculated for strain SE385 using MICs of vancomycin of 2 mg/liter and a with strains SE284 and SE385, respectively, while vancomycin did
vancomycin dose of 440 mg/kg/day. not show bactericidal activity until 24 h with any strain. Moreover,
d Three mice every time point. these results may be related to the ability of daptomycin to pene-

February 2012 Volume 56 Number 2 aac.asm.org 615

Domínguez-Herrera et al.
TABLE 2 Efficacies of daptomycin and vancomycin in a murine model of foreign-body infection caused by strains SE284 and SE385
Bacterial concn (mean ⫾ SD)
Strain Treatment No. of xxx Liver (log10 CFU/g)
SE284 Control 15 9.39 ⫾ 0.52
Daptomycin 14 1.69 ⫾ 2.28a
Vancomycin 14 4.20 ⫾ 3.12a
SE385 Control 14 9.93 ⫾ 0.88
Daptomycin 15 1.66 ⫾ 2.81a,b
Vancomycin 14 4.56 ⫾ 2.61a
a P ⬍ 0.05 compared with the internal control group.
b P ⬍ 0.05 compared with the vancomycin group.
trate S. epidermidis biofilms (21), compared with the reduced abil-
ity of vancomycin to penetrate biofilms (20).
Foreign-body infections caused by MRSE strains are difficult
to treat, mainly because of the presence of biofilm and bacterial
tolerance to antibiotics (22). To date, vancomycin is the treatment
of reference against MRSE infections, but several studies have
pointed out its potential toxicity, limited bactericidal killing, and
low capacity to cross biofilms as well as the inability to reach op-
timal pharmacodynamic parameters due to the increasing MIC of
vancomycin against MRSE strains (1, 14, 19). On the basis of
previous experimental studies, daptomycin currently plays a key
role in the treatment of skin and soft-tissue infections caused by S.
aureus (18a). In this context, daptomycin would appear to be a
safer and more effective alternative anti-MRSE treatment. How-
ever, its efficacy against these difficult-to-treat infections is scarce
and limited to experimental models (8).
Similar results were found by Garcia-de-la-María et al. in an
experimental endocarditis model in rabbits using an MRSE strain
(8). Those researchers evaluated the efficacies of 6 and 10 mg/kg of
daptomycin and 30 and 60 mg/kg of vancomycin, simulating the
human doses, and they observed a higher percentage of sterile
vegetations with daptomycin than with vancomycin (8). Other
authors evaluated the efficacy of daptomycin and vancomycin in
an experimental rat model of central venous catheter biofilms
with antibiotic-lock therapy combined with systemic therapy
against MRSE (24) and concluded that daptomycin has an activity
similar to that of vancomycin for the eradication of infection in
central venous catheters and in catheter-related metastatic infec-
tion or bacteremia (24).
Using a model of tissue cage infection in guinea pigs, Olson et
al. showed a failure of treatment with daptomycin and vancomy-
cin against two isogenic S. epidermidis strains, a biofilm-
producing strain and a non-biofilm-producing strain (17). How-
ever, those authors did not determine the susceptibility of the
strains and used lower doses of daptomycin and vancomycin (5
and 15 mg/kg, respectively), without previous pharmacokinetic
and pharmacodynamic studies (17). On the contrary, the addition
of rifampin to daptomycin or vancomycin sterilized 5/6 tissues
cages colonized with biofilm-producing S. epidermidis.
In summary, the present study shows that daptomycin is more
effective than vancomycin for the treatment of experimental
foreign-body infection causing bacterial systemic infection by
biofilm-producing MRSE strains with reduced susceptibility to
vancomycin. However, only randomized clinical trials may eluci-
date whether daptomycin is better than vancomycin for the treat-
616 aac.asm.org
Sterile blood
Catheter (log10 CFU/ml) cultures (%) Survival (%)
6.56 ⫾ 0.65 0 0
0.69 ⫾ 1.22a,b 86.7a 66.7a
3.69 ⫾ 2.70a 57.1a 42.9a
5.98 ⫾ 0.90 0 0
0.42 ⫾ 1.26a 100a 93.3a
1.20 ⫾ 1.92a 76.9a 76.9a
ment of foreign-body infections caused by methicillin-resistant S.
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epidermidis.
ACKNOWLEDGMENTS
This study was supported by a research grant from Novartis Farmacéutica
S.A. (Barcelona, Spain) and by the Ministerio de Ciencia e Innovación,
Instituto de Salud Carlos III, cofinanced by the European Development
Regional Fund “A Way to Achieve Europe” ERDF, Spanish Network for
the Research in Infectious Diseases (REIPI RD06/0008/0000).
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